Platelets and Megakaryocytes Contain Functional Nuclear Factor-κB

Objective-To investigate the presence and role of NF-kappa B proteins in megakaryocytes and platelets. The nuclear factor-kappa B (NF-kappa B) transcription factor family is well known for its role in eliciting inflammation and promoting cell survival. We discovered that human megakaryocytes and platelets express the majority of NF-kappa B family members, including the regulatory inhibitor-kappa B (I-kappa B) and I-kappa kinase (IKK) molecules. Methods and Results-Anucleate platelets exposed to NF-kappa B inhibitors demonstrated impaired fundamental functions involved in repairing vascular injury and thrombus formation. Specifically, NF-kappa B inhibition diminished lamellapodia formation, decreased clot retraction times, and reduced thrombus stability. Moreover, inhibition of I-kappa B-alpha phosphorylation (BAY-11-7082) reverted fully spread platelets back to a spheroid morphology. Addition of recombinant IKK-beta or I-kappa B-alpha protein to BAY inhibitor-treated platelets partially restored platelet spreading in I-kappa B-alpha inhibited platelets, and addition of active IKK-beta increased endogenous I-kappa B-alpha phosphorylation levels. Conclusion-These novel findings support a crucial and nonclassical role for the NF-kappa B family in modulating platelet function and reveal that platelets are sensitive to NF-kappa B inhibitors. As NF-kappa B inhibitors are being developed as antiinflammatory and anticancer agents, they may have unintended effects on platelets. On the basis of these data, NF-kappa B is also identified as a new target to dampen unwanted platelet activation. (Arterioscler Thromb Vasc Biol. 2010;30:591-598.)